Field of the Invention
The present invention concerns the field of tumor therapeutics and diagnostics. Specifically, it relates to a peptide comprising at least 8 amino acids in length which are present as contiguous amino acid sequence in the human Isocitratdehydrogenase Type 1 (IDH1), wherein said peptide has at least one amino acid exchange from R to H at a position corresponding to position 132, for use in preventing and/or treating a cancer. Further contemplated is a medicament comprising the said peptide. Furthermore, the invention relates to a method for diagnosing cancer characterized by having a mutation in the genome of at least some cancer cells which results in the expression of a mutant IDH1 having the R132H mutation comprising the steps of contacting a blood sample of a subject suspected to suffer from such a tumor with a peptide comprising at least 10 amino acids in length which are present as contiguous amino acid sequence in the IDH1, wherein said peptide has at least one amino acid exchange from R to H at a position corresponding to position 132 for a time and under conditions which allow for specific binding of a component of the immune system to the peptide, and determining whether, or not, binding of the said component of the immune system to the peptide occurred, wherein the cancer is diagnosed if the occurrence of binding has been determined. Provided by the invention is also a kit and a device for carrying out said method.
Description of Related Art
Mutations in the gene encoding cytosolic NADP+ dependent isocitrate dehydrogenase (IDH1) emerged as an unsuspected finding in sequence analysis of glioblastoma (GBM) (Parsons 2008, Science 321(5897):1807-12). Recent studies reported on mutations in the IDH1 gene resulting in an amino acid exchange in position 132 in about 70% of anaplastic gliomas and 12% of glioblastomas (Balls 2008, Acta Neuropathol. 116(6):597-602, Yan 2009, N Engl J Med. 360(8):765-73, Watanabe 2009, Am J Pathol. 174(4):1149-53, De Carli 2009, N Engl J Med. 360(21):2248, Ducray 2009, N Engl J Med. 360(21):2248, Hartmann 2009, Acta Neuropathol. 118(4):469-74, Ichimura 2009, Neuro Oncol. 11(4):341-7, Sanson 2009, J Clin Oncol. 27(25):4150-4).
Isocitrate dehydrogenase catalyzes the oxidative decarboxylation of isocitrate to alpha-ketoglutarate using reducing NADP+ to NADPH. Mutations affecting the amino acid arginine at position 132 of the amino acid sequence, which belongs to an evolutionary conserved region located to the binding site of isocitrate. The mutations reported always were heterozygous and alterations suggestive for protein inactivation, such as splice site or nonsense mutations, were not detected, thus prompting speculations on an activating nature of the mutation. However, the measurement of enzymatic activity showed an inactivating effect of the mutation (Yan 2009, N Engl J Med. 360(8):765-73). However, the role of IDH1 in cancer development and/or progression remains elusive.
IDH1 mutations occur in a high frequency in WHO grade II and III diffuse gliomas. 93% of all IDH1 mutations are characterized by an amino acid exchange R132H (Hartmann 2009, Acta Neuropathol. 118(4):469-74).
Effective therapies against the aforementioned cancer types and others, which are accompanied by IDH1 R132H would be highly desirable since these cancers are most often aggressive cancers with poor outcome prognosis.
The current diagnostic measures for the aforementioned cancer types and, in particular, the diagnostic means for determining whether a cancer is accompanied by an IDH1 R132H mutation, are pivotally based on either genomic DNA sequencing approaches or immunohistological staining methods (see, e.g., EP 2 256 214 A2). Both techniques, however, require proper tissue samples from the cancer tissue which are obtainable, only, via cumbersome and potentially dangerous biopsy. Thus, a reliable and efficient diagnostic measure for those types of cancer would also be desirable.
The technical problem underlying the present invention can be seen as the provision of therapeutic and diagnostic means and methods complying with the aforementioned needs. The technical problem is solved by the embodiments characterized in the claims and herein below.